1. Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug
- Author
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Stephen J. Lippard, Mikael J. Pittet, Yoshiko Iwamoto, Nagesh Kolishetti, Camilla Engblom, Rainer H. Kohler, Suresh Gadde, Bjorn Askevold, Katherine S. Yang, Christina Pfirschke, Harshal Zope, Ralph Weissleder, Omid C. Farokhzad, Yao-Rong Zheng, Miles A. Miller, Massachusetts Institute of Technology. Department of Chemistry, Zheng, Yao-Rong, and Lippard, Stephen J.
- Subjects
Drug ,DNA damage ,media_common.quotation_subject ,Mice, Nude ,General Physics and Astronomy ,Antineoplastic Agents ,Pharmacology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Drug Delivery Systems ,Pharmacokinetics ,In vivo ,Cell Line, Tumor ,Neoplasms ,Animals ,Humans ,Prodrugs ,Platinum ,Mice nude ,media_common ,Multidisciplinary ,Chemistry ,Macrophages ,General Chemistry ,Prodrug ,3. Good health ,Mice, Inbred C57BL ,Cell culture ,Drug delivery ,Nanoparticles ,Female - Abstract
Therapeutic nanoparticles (TNPs) aim to deliver drugs more safely and effectively to cancers, yet clinical results have been unpredictable owing to limited in vivo understanding. Here we use single-cell imaging of intratumoral TNP pharmacokinetics and pharmacodynamics to better comprehend their heterogeneous behaviour. Model TNPs comprising a fluorescent platinum(IV) pro-drug and a clinically tested polymer platform (PLGA-b-PEG) promote long drug circulation and alter accumulation by directing cellular uptake toward tumour-associated macrophages (TAMs). Simultaneous imaging of TNP vehicle, its drug payload and single-cell DNA damage response reveals that TAMs serve as a local drug depot that accumulates significant vehicle from which DNA-damaging Pt payload gradually releases to neighbouring tumour cells. Correspondingly, TAM depletion reduces intratumoral TNP accumulation and efficacy. Thus, nanotherapeutics co-opt TAMs for drug delivery, which has implications for TNP design and for selecting patients into trials., Drug-loaded nanoparticles allow controlled release and enhanced delivery, yet understanding in vivo behavior has been difficult. Here, the authors develop a platinum prodrug coupled to a polymer platform, and use intravital imaging to show that the nanoparticle accumulates in macrophages, from the which drug redistributes to neighboring tumour cells.
- Published
- 2015